Hybrid mathematical modeling for cell fate determination in clustered cell migration

University Of Maryland Baltimore County, Baltimore MD

Investigators

Abstract

Fate of the cell, arguably the most basic building block of life, is guided by many things, internal drive and external influences among them. As cells grow in community, differences arise and roles are established. How are different roles established? What influences are paramount in deciding? What is the interplay of roles and influences that produces the growing pattern, in time and space? Mathematics seeks to discover patterns and applying mathematical modeling to cells that are fated to migrate and travel in clusters will describe the balance between intrinsic and extrinsic signals. In domains that are challenging to visualize in experiments and that change over time, theory and computation can guide discovery of the principles at work determining cell fate and decision-making, ultimately to facilitate normal development and to hinder malignant growth. This research will also train diverse researchers to fulfill their roles in scientific discovery. Successful cell migration is critical for human development, immune response, and advancement of some diseases, but much remains unknown. In particular, there are many gaps in our knowledge of how cells navigate in vivo through complex tissue environments over time. This project will leverage mathematical modeling and the simple, genetically tractable, Drosophila ovary to address open questions about how cells acquire motility, coordinate behaviors with neighboring cells, and move within an organ. In many cases communication about these behaviors between cells must occur through the extracellular space. It is unclear how extracellular signaling molecules, such as chemoattractants and cytokines, are distributed in tissues, and how spatially dependent differences in concentration may affect signaling. For example, extracellular signal, such Unpaired (UPD), can interact with the transmembrane Janus Kinase (JAK) to activate the Signal Transducer and Activator of Transcription (STAT) responsible for the cell fate motility decision. The hypothesis is that the heteromorphic extracellular domain impacts signal distribution and motile cell behaviors, which can be revealed through a hybrid agent-based model coupled to a reaction-diffusion model of extracellular signal converted to intracellular signalling and movement. Based on imaging data, we will accurately model heterogeneity in tissue structure and examine the impact of this physical constraint on molecular diffusion and signaling. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.